Neurexins are presynaptic adhesion molecules that perform central functions in regulating synapse properties. Neurexins control properties of synapses as diverse as the presynaptic release probability, the postsynaptic receptor composition, trans-synaptic endocannabinoid signaling, and synapse numbers. Puzzlingly, the functions of neurexins differ among synapses and depend on the identity of the pre- and postsynaptic neurons. Moreover, mutations of neurexin genes, especially NRXN1, are among the most important single-gene risk factors for schizophrenia, autism, and Tourette syndrome. Hundreds of recent studies have examined the biological role of neurexins, but their function in shaping synapses remains unclear. For example, it is still unknown what range of functions neurexins perform, how neurexins perform these functions, and why mutations in neurexin genes predispose to neuropsychiatric disorders. Addressing these questions is essential for insight into how synaptic circuits operate and is the goal of the current grant application. Extracellularly, neurexins interact with more than 30 ligands to form trans-synaptic adhesion complexes. These ligands include key regulators of synapses such as neuroligins, cerebellins, and LRRTMs. By binding to these ligands, neurexins form a molecular network of interactions that is activity-dependent and that likely mediates their diverse functions. Neurexins are diversified into thousands of isoforms by alternative splicing that is, at least in part, also activity-dependent and regulates the ligand-binding affinity of neurexins. Given the central role of neurexins in shaping synapses, the present application thus aims to test the overarching hypothesis that neurexins are master regulators of synapse properties that control synaptic information processing and circuit input/output relationships in an activity-dependent manner by binding to diverse ligands. In four specific aims, the application proposes experiments that will investigate the overall functions of all neurexin genes, study the role of selected interactions of neurexins with key ligands, examine the regulation and functional significance of the extensive alternative splicing of neurexins, and test the mechanisms of regulation of neurexins by post-translational modifications. These experiments will systematically characterize neurexin functions in three brain areas, the hippocampus, olfactory bulb, and medial nucleus of the trapezoid body in the brainstem, using mutant mice as a model system. The experiments will adopt a multidisciplinary approach that combines optical imaging with protein chemistry and electrophysiology to explore the full functions of neurexins. They will aim to reveal the scope and mechanisms of neurexin functions and to characterize the implications of these functions for synaptic circuits. Among others, these experiments will contribute to our understanding of how a synapse?s properties are shaped dynamically by neurexins in an activity-dependent manner that determines the input/output relations of the neural circuits in which this synapse resides, and will add to our understanding of how neurexin mutations predispose to neuropsychiatric disorders.